Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) is a protein secreted by many cell types which has been shown in model systems unrelated to the nervous system to perform two major functions: it is an angiogenic, endothelial-specific growth factor, and a potent inducer of vascular leakage. We have shown that VEGF is upregulated in brain tumors and in reactive astrocytes resulting from CNS injuries, indicating that increased VEGF expression may underlie the increased permeability and angiogenesis associated with these conditions. Our continuing goals are to define the function of VEGF in the central nervous system, to understand the extent to which altered expression of VEGF contributes to the development of certain pathologic conditions, and to develop strategies for modifying the activity of VEGF in appropriate clinical settings. In order to study the effects of VEGF on normal brain we infused VEGF intrastriatally using miniosmotic pumps. This chronic overexposure of the normal rodent brain to VEGF greatly increased the capillary permeability and caused focal blood- brain barrier (BBB) disruption without cell destruction or inflammation. While VEGF itself was not inflammatory, it promoted inflammation in the brain when given in combination with a foreign antigen such as a virus, suggesting that by opening the BBB, VEGF allows recognition of antigens in the brain which would otherwise remain sequestered. The findings that VEGF 1) is upregulated in reactive astrocytes and 2) can modulate the immune response in the brain, led us to hypothesize that VEGF might be involved in the development of multiple sclerosis (MS), since MS lesions are characterized by astrogliosis, focal BBB disruption, and inflammation. Immunohistochemical examination of MS plaques with anti-VEGF antibodies revealed increased VEGF expression specifically in astrocytes associated with the lesions, but not in normal white matter, suggesting a role for altered VEGF expression in the pathogenesis of this disease. Since previous results have demonstrated the upregulation of VEGF receptors in brain tumor-associated vessels compared to normal brain, we have developed a VEGF-toxin conjugate as a possible therapeutic agent to treat brain tumors. This toxin is capable of killing endothelial cells in vitro with an ED50 of 10-12 M while sparing other cell types. Chronic intracerebral infusion of VEGF-toxin into normal rat brains for 7 days at concentrations as high as 10-7 M resulted in minimal histologic changes and no neurologic deficits. This result is consistent with the lack of VEGF receptor expression and angiogenesis in the normal brain. Direct infusion of VEGF-toxin into 9L gliosarcoma flank tumors resulted in destruction of tumor vasculature as determined by decreased vessel density and necrosis of the tumor tissue. Use of VEGF-toxin for the treatment of VEGF/angiogenesis-dependent intracranial tumors appears promising.